The Role of Notch in the Cardiovascular System: Potential Adverse Effects of Investigational Notch Inhibitors

Abstract

Targeting the Notch pathway is a new promising therapeutic approach for cancer patients. Inhibition of Notch is effective in the oncology setting because it causes a reduction of highly proliferative tumor cells and it inhibits survival of cancer stem cells, which are considered responsible for tumor recurrence and metastasis. Additionally, since Delta-like ligand 4 (Dll4)-activated Notch signaling is a major modulator of angiogenesis, anti-Dll4 agents are being investigated to reduce vascularization of the tumor. Notch plays a major role in the heart during the development and, after birth, in response to cardiac damage. Therefore, agents used to inhibit Notch in the tumors (gamma secretase inhibitors and anti-Dll4 agents) could potentially affect myocardial repair. The past experience with trastuzumab and other tyrosine kinase inhibitors used for cancer therapy demonstrates that the possible cardiotoxicity of agents targeting shared pathways between cancer and heart and the vasculature should be considered. To date, Notch inhibition in cancer patients has resulted only in mild gastrointestinal toxicity. Little is known about the potential long-term cardiotoxicity associated to Notch inhibition in cancer patients. In this review, we will focus on mechanisms through which inhibition of Notch signaling could lead to cardiomyocytes and endothelial dysfunctions. These adverse effects could contrast with the benefits of therapeutic responses in cancer cells during times of increased cardiac stress and/or in the presence of cardiovascular risk factor.

The emerging role of Notch pathway in ageing: Focus on the related mechanisms in age-related diseases

“…This in turn activates the transcription of specific Notch target genes, such as Hes (hairy/enhancer of split), Hey (Hes-related proteins), Nrarp (Notch-regulated andrin repeat protein), cMyc, cyclin D1, and many other genes. Indeed, the spectrum of immediate notch targets is large and several genes may be activated in parallel, including those encoding repressor transcription factors like Snail1 (Sahlgren et al, 2008), p21 (Rangarajan et al, 2001) or c-Myc, with a context-dependent activator or repressor function (Weng et al, 2006). are the critical determinants for interactions with ligands.…”

Circulating delta-like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus-based immunosuppression

“…8 However, the clinical benefit of EVR in HTx correlates poorly with changes in circulating inflammatory and vascular markers, and the mechanism by which EVR slows CAV progression remains unrevealed. 5 The Notch signaling pathway is essential for communication between neighboring cells 9 and processes known to contribute to CAV, 10 like EC activation, 11 accumulation and activation of immune cells, 12 proliferation of VSMCs, extracellular matrix (ECM) remodeling 13,14 and T cell activation. 15 Activation or inhibition of Notch signaling depends on the configuration and interactions of canonical Notch ligands.…”

Spheroid three-dimensional culture enhances Notch signaling in cardiac progenitor cells

“…[14] However, its reactivation after myocardial damage indicates that Notch plays a key role in cardiac repair. [13,17] In CPCs, activation of the Notch pathway is known to induce cell proliferation, [13] and is needed for the onset of cardiomyogenic differentiation, at the same time maintaining the cells in a proliferative state. [13] Here we use CSps, of both adult (CSps) and fetal origin (CMPC-CSps), as a model to investigate the Notch pathway in CPCs under room air (20% O 2 ) and tissue physiological (5% O 2 ) oxygen tension (often referred to as "hypoxia").…”